3T MRI investigation of cardiac left ventricular structure and function in a UK population:The tayside screening for the prevention of cardiac events (TASCFORCE) study

Contract grant sponsor: Souter Charitable Trust, and Chest, Heart and Stroke Scotland; Contract grant sponsor: Wellcome Trust; contract grant number: WT 085664 (Clinical Research Fellowship to J.W-McC.)Purpose : To scan a volunteer population using 3.0T magnetic resonance imaging (MRI). MRI of the left ventricular (LV) structure and function in healthy volunteers has been reported extensively at 1.5T. Materials and Methods : A population of 1528 volunteers was scanned. A standardized approach was taken to acquire steady-state free precession (SSFP) LV data in the short-axis plane, and images were quantified using commercial software. Six observers undertook the segmentation analysis. Results : Mean values (±standard deviation, SD) were: ejection fraction (EF) = 69 ± 6%, end diastolic volume index (EDVI) = 71 ± 13 ml/m2 , end systolic volume index (ESVI) = 22 ± 7 ml/m2 , stroke volume index (SVI) = 49 ± 8 ml/m2 , and LV mass index (LVMI) = 55 ± 12 g/m2 . The mean EF was slightly larger for females (69%) than for males (68%), but all other variables were smaller for females (EDVI 68v77 ml/m2 , ESVI 21v25 ml/m2 , SVI 46v52 ml/m2 , LVMI 49v64 g/m2, all P < 0.05). The mean LV volume data mostly decreased with each age decade (EDVI males: -2.9 ± 1.3 ml/m2 , females: -3.1 ± 0.8 ml/m2 ; ESVI males: -1.3 ± 0.7 ml/m2 , females: -1.7 ± 0.5 ml/m2 ; SVI males: -1.7 ± 0.9 ml/m2 , females: -1.4 ± 0.6 ml/m2 ; LVMI males: -1.6 ± 1.1 g/m2 , females: -0.2 ± 0.6 g/m2 but the mean EF was virtually stable in males (0.6 ± 0.6%) and rose slightly in females (1.2 ± 0.5%) with age. Conclusion : LV reference ranges are provided in this population-based MR study at 3.0T. The variables are similar to those described at 1.5T, including variations with age and gender. These data may help to support future population-based MR research studies that involve the use of 3.0T MRI scanners.Publisher PDFPeer reviewe

Comparative Pharmacokinetics and Pharmacodynamics of Amlodipine in Hypertensive Patients with and without Type II Diabetes Mellitus

Recent clinical trials aimed at attenuating complications in diabetes mellitus have generated interest in the impact of drug formulation and altered pharmacokinetics and pharmacodynamics in diabetes. Specifically, it has been proposed that the diabetic state may alter the pharmacokinetics of several cardiovascular drugs, including some calcium antagonists. The present study investigates the effects of diabetes mellitus on the pharmacokinetics and pharmacodynamics of amlodipine in hypertensive subjects with and without diabetes mellitus to determine whether the diabetic state alters these parameters. This trial consisted of a 2-week placebo washout phase, a 2-week titration phase, and a 2-week maintenance phase. Study patients included 18 hypertensive patients with type II diabetes mellitus and 10 nondiabetic hypertensive patients. Blood samples were collected after administration of amlodipine and AUC, Cmax, and tmax were determined. The acute 24-hour pharmacodynamic response to amlodipine was assessed by blood pressure and telemetric heart rate measurements. There were no significant differences for either amlodipine 5 or 10 mg in AUC (p = 0.40 for 5 mg;p = 0.59 for 10mg), Cmax (p = 0.41 for 5mg; p = 0.45 for 10 mg), and tmax (p = 0.79 for 5mg; p = 0.67 for 10 mg) between diabetic and nondiabetic hypertensive subjects. Similarly, the 24-hour pharmacodynamic effects of amlodipine on systolic blood pressure, diastolic blood pressure, and heart rate did not differ between diabetic and nondiabetic subjects as assessed by repeated-measures analysis of variance. Because of the theoretical basis for anticipating that diabetes mellitus may provoke important pharmacokinetic and pharmacodynamic alterations, our study provides an important database in clearly demonstrating that the diabetic milieu did not alter the pharmacokinetics or pharmacodynamics of amlodipine

P-259: Effects of type II diabetes mellitus on the comparative pharmacokinetics and pharmacodynamics of amlodipine in hypertensive patients

Introduction: Recent clinical trials aimed at attenuating complications in diabetes mellitus have generated interest in the impact of drug formulation on altered pharmacokinetics (PK) and pharmacodynamics (PD) in diabetes. This study investigates the PK and PD of amlodipine in hypertensive subjects with and without diabetes mellitus to determine whether the diabetic state alters these parameters. Methods: Two-week placebo wash-out phase, two week titration phase, and two-week maintenance phases. Patients included 18 hypertensive patients with Type II diabetes mellitus and 10 nondiabetic hypertensive patients. Patients were admitted to the University of Miami Division of Clinical Pharmacology Research Center for 24-hour PK and PD studies. AUC, Cmax, and Tmax were analyzed for differences between hypertensive patients with and without diabetes on day 28 when all 28 subjects received amlodipine 5 mg and at day 42 for the 21 subjects who received amlodpine 10mg. The acute PD response to amlodipine was assessed by systolic and diastolic blood pressure changes and by telemetric heart rate monitoring. Results: There were no significant differences for either amlodipine 5 or 10 mg in AUC, Cmax, and Tmax between diabetic and non-diabetic hypertensive subjects. The 24-hour pharmacodynamic effects of amlodipine on systolic blood pressure, diastolic blood pressure, and telemetric heart rate did not differ between diabetic and nondiabetic subjects as assessed by repeated measures analysis of variance. Conclusion: Because of the theoretical basis for anticipating that diabetes mellitus may provoke important pharmacokinetic and pharmacodynamic alterations, our study provides an important data base in clearly demonstrating that the diabetic milieu did not alter the pharmacokinetics or pharmacodynamics of amlodipine. Whether diabetes mellitus alters the PK or PD of other dihydropyridines remains to be studied. (See Table) Amlodipine 5 mg (day 28) DM No DM p-value AUC (hr*ng/ml) 304.1 (165.3) 252.5 (121.2) .40 Cmax (ng/ml) 16.6 (9.4) 13.7 (7.5) .41 Tmax (hr) 8.2 (2.4) 8.6 (5.0) .79 Amlodipine 10 mg (day 42) AUC (hr*ng/ml) 584.0 (244.6) 525.4 (234.0) .59 Cmax (ng/ml) 31.6 (13.2) 27.2 (11.8) .45 Tmax (hr) 7.2 (2.0) 7.8 (4.4) .6

The pharmacokinetics and hemodynamics of sildenafil citrate in male hemodialysis patients

The pharmacokinetics and hemodynamics of sildenafil citrate in male hemodialysis patients.BackgroundErectile dysfunction (ED) is highly prevalent in men with renal disease. The clearance of sildenafil citrate, a highly effective oral treatment for ED, is decreased in men with severe renal insufficiency, but the pharmacokinetic and hemodynamic profiles during maintenance hemodialysis in men with end-stage renal disease have not been studied.MethodsFifteen men undergoing chronic outpatient maintenance hemodialysis received a single 50-mg oral dose of sildenafil on 2 occasions, once 2 hours before, and once 2 hours after hemodialysis, with randomized assignment to sequence. Blood and dialysate samples were collected, and hemodynamic measurements were made.ResultsHemodialysis did not significantly clear either sildenafil or its primary metabolite, UK-103,320. Administration after hemodialysis was associated with a 17% higher peak plasma concentration and earlier time to peak, which were not clinically meaningful, whereas the overall extent of absorption and the elimination half-life were not affected. The average extent of drug bound to plasma protein was approximately 96% in hemodialysis patients. Intradialytic hypotension was not observed more frequently when sildenafil was administered before hemodialysis. Systolic blood pressure tended to decrease less during hemodialysis when subjects were treated with sildenafil before dialysis.ConclusionThe present study demonstrates that sildenafil is not cleared by hemodialysis, and the pharmacokinetic profile resembles more closely that observed in normal volunteers than that observed in patients with severe renal insufficiency. In addition, we found that sildenafil does not promote intradialytic hypotension